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Wonderful, rigorous study, and perhaps a window into the future of neurodegeneration research. Though the thought is slightly disturbing, it is becoming more and more apparent that the aggregates, plaques, and tangles that we neuropathologists love to see (and preach about) may not be as important as we thought.

I would like to add this recent study, which showed that nucleic acid binding activity is required for TDP-43-mediated toxicity in flies.

C-terminal fragments of TDP-43 lack such activity, but are still capable of forming aggregates. This supports the hypothesis that the aggregates themselves are not toxic, and that instead, the toxicity is related to a modulation of the endogenous function of this nucleic acid binding protein.

Therefore, studies addressing its DNA and RNA targets may be very important in understanding TDP-43-mediated neurodegeneration.